Comparative analysis of late-stage rheumatoid arthritis and osteoarthritis reveals shared histopathological features.

OBJECTIVES: Osteoarthritis (OA) is a debilitating and heterogeneous condition, characterized by various levels of articular cartilage degradation, osteophytes formation, and synovial inflammation. Multiple evidences suggest that synovitis may appear early in the disease development and correlates with disease severity and pain, therefore representing a relevant therapeutic target. In a typical synovitis-driven joint disease, namely rheumatoid arthritis (RA), several pathotypes have been described by our group and associated with clinical phenotypes, disease progression, and response to therapy. However, whether these pathotypes can be also observed in the OA synovium is currently unknown. METHODS: Here, using histological approaches combined with semi-quantitative scoring and quantitative digital image analyses, we comparatively characterize the immune cell infiltration in a large cohort of OA and RA synovial tissue samples collected at the time of total joint replacement. RESULTS: We demonstrate that OA synovium can be categorized also into three pathotypes and characterized by disease- and stage-specific features. Moreover, we revealed that pathotypes specifically reflect distinct levels of peripheral inflammation. CONCLUSIONS: In this study, we provide a novel and relevant pathological classification of OA synovial inflammation. Further studies investigating synovial molecular pathology in OA may contribute to the development of disease-modifying therapies.

Reliability of pain scores during a body weight support protocol in individuals with knee osteoarthritis.

PURPOSE: To explore the reliability of percentage of Body Weight Support (BWS) needed for maximal pain relief and of pain scores across 12 walking conditions including pre and post-over-ground walking and an unweighting protocol from 0% to 40% BWS on a lower body positive pressure (LBPP) treadmill for individuals with knee osteoarthritis (OA). MATERIALS AND METHODS: Twenty individuals (64 ± 9.44 years) with knee OA completed over-ground walking and an unweighting protocol on an LBPP treadmill. The amount of BWS started at 0% and increased by 5% increments until it reached 40%. Pain scores were recorded at the end of each increment. RESULTS: The reliability of pain scores was assessed using a Spearman's rho. This study found moderate reliability of the percentage of BWS for maximal pain relief. Additionally, there was good reliability of pain scores with pre and post-over-ground walking and from 0% BWS to 30% BWS, but moderate reliability of pain scores was found at 35% and 40% BWS. CONCLUSION: This study supports the use of pain scores as a reliable measure during an unweighted walking session on an LBPP treadmill.IMPLICATIONS FOR REHABILITATIONBoth the OARSI and ACR recommend exercise in the treatment of individuals with knee OA but acknowledge that pain during exercise and exercise preference/accessibility are important when considering the type of exercise for an individual.LBPP treadmills decrease pain in individuals with knee OA during walking.Pain scores during unweighted walking show moderate to good reliability for individuals with knee OA.This study provides an unweighting protocol to use clinically to determine the Body Weight Support needed to decrease pain.

An outbreak of Shiga toxin-producing Escherichia coli O157:H7 linked to a mud-based obstacle course, England, August 2018.

In August 2018, Public Health England (PHE) was made aware of five probable cases of Shiga toxin-producing Escherichia coli (STEC) O157:H7 among individuals reporting participation in a mud-based obstacle race. An additional four cases, identified via routine whole-genome sequencing, were subsequently linked to the same event. Two of the nine cases were due to secondary household transmission. Despite an agreement between the event organizers and the local authority, to ensure that all livestock were removed from the site 28 days before the event, sheep were observed grazing on some of the routes taken by the runners 2 days prior to the race taking place. A retrospective review of incidents reported to PHE between 2015 and 2018 identified 41 cases of gastroenteritis associated with muddy assault course events. Of these, 25 cases were due to infection with STEC O157:H7, of which all but one were associated with outbreaks. Due to the environment in which such events take place, it is impossible to entirely remove the risk of exposure to potentially pathogenic zoonoses. However, race organizers should ensure that livestock are removed from the course 28 days before the event. They should also ensure that participants are made aware of the risk of contracting gastrointestinal disease from the environment, and to stress the importance of hand hygiene post-event and the risk of secondary transmission, particularly to children who are at risk of developing haemolytic uraemic syndrome.

Creating innovative clinical nurse leader practicum experiences through academic and practice partnerships.

INTRODUCTION: The new Clinical Nurse Leader (CNL) nursing role was developed to meet the complex health care needs of patients, families, and health care systems. CASE PRESENTATION: This article describes the process used by nurse leaders at the University of Alabama at Birmingham School of Nursing and Hospital to develop Model C CNL practicum courses, recruit and prepare clinical preceptors, prepare clinical microsystems for CNL students, and develop additional practice partnerships throughout the region. MANAGEMENT AND OUTCOME: Critical to the success of the CNL role is a dynamic partnership between academic and practice leaders.The partnership allows faculty to develop curricula that are relevant and responsive to the rapidly changing health care system. Clinical leaders become more aware of trends and issues in nursing education. DISCUSSION: Continued growth and success of the CNL role is largely dependent on the ability of faculty and practice partners to collaborate on innovative educational programs and models of care delivery.

Discovery of a novel and potent class of FabI-directed antibacterial agents.

Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.

Confirmation of the antibacterial mode of action of SB-219383, a novel tyrosyl tRNA synthetase inhibitor from a Micromonospora sp.

The compound designated SB-219383 is a potent and selective inhibitor of bacterial tyrosyl tRNA synthetases. It exhibits an IC50 of < 1 nM against Staphylococcus aureus tyrosyl tRNA synthetase and weak in vitro activity against Staphylococci and Streptococci. Here we present data consistent with SB-219383 eliciting an amino acid starvation in both S. aureus and Streptococcus pneumoniae, supporting the conclusion that the antibacterial activity of SB-219383 is due to tyrosyl tRNA synthetase inhibition.

The effect of antibiotic treatment on the intracellular nucleotide pools of Staphylococcus aureus.

In an assessment of antibiotic action on Staphylococcus aureus, we found that distinct changes in intracellular nucleotide pools occur depending on the antibiotic mode of action. In particular, we have quantitated the effect of antibiotics on pools of the nucleotide guanosine 3'-diphosphate, 5'-triphosphate (pppGpp). Intracellular pppGpp levels increased in response to treatment with the isoleucyl tRNA synthetase inhibitor mupirocin, the uncoupler carbonyl cyanide-m-chlorophenylhydrazone, and rifampicin. These compounds were distinguishable by the degree in which they increased the pppGpp pool and by their differential effect on the pools of other nucleotides. This technique has been used to confirm and to refute the expected mode of action of several compounds identified as possible inhibitors of tRNA synthetases. Our results provide the framework for using nucleotide analysis in the assessment of novel antimicrobial compounds with unknown modes of action.